Antarctic lichens are known to produce unique secondary metabolites different from those produced by higher plants (Ingolfsdottir, K., Phytochemistry, 61:729, 2002). The secondary metabolites produced by these lichens mostly belong to the chemical classes of depsides, depsidones, and dibenzofurans, and these compounds are supposed to be associated with the low growth rate of lichens (Kumar, K. C. S. et al., J. Nat. Prod., 62:817, 1999; Huneck, S., Naturwissenschaften, 86:559, 1999). In addition, the various biological activities of lichens, including antibiotic, antimycobacterial, antiviral, pain-killing, and antipyretic activities, and so on were found in screening processes (Ingolfsdottir, K., Phytochemistry, 61:729, 2002; Kumar, K. C. S. et al., J. Nat. Prod., 62:817, 1999). Thus, Interest has grown in the development of medical drugs using lichen metabolites.
Meanwhile, diabetes is metabolic disorder symptom, including hyperglycemia, which results from defects in insulin action, insulin secretion, or both. Also, diabetes is more likely to cause vascular complications in the future and can be mostly divided into type 1 diabetes and type 2 diabetes. The type 1 (insulin-dependent) diabetes is caused by immune-mediated destruction of beta cells in the pancreas and the absolute deficiency of insulin accordingly, and the type 2 (non-insulin-dependent) diabetes is developed when the body produces insulin but not enough or cannot use it properly. In the state of insulin resistance in which the body's cells do not respond to insulin properly, the utilization of energy sources, particularly sugars, in the body, is insufficient so that energy required for the body is deficient, and excess sugars accumulate in blood and are released with urine. Thus, diabetes is one of chronic degenerative diseases that are difficult to be cured by the roots.
The World Health Organization (WHO) and the United Nations (UN) emphasize that the number of diabetic patients in the world would reach about 246 millions at the end of the year 2007, and that the prevention of the onset of diabetes, strict regulation of blood glucose levels, and prevention of complications resulting from diabetes are important as the number of deaths caused by diabetes increases gradually year by year. In addition, the Korean Diabetes Association and the Korean Health Insurance Review Assessment Service reported that the total number of diabetic patients in 2003 in Korea was 4.01 millions and that the number of diabetic patients in Korea will reach 7.2 millions in 2030, which correspond to one out of every seven people of the Korean population. Especially, a rapid increase in medical expenses has a close connection with an explosive increase in the number of diabetic patients as well as a continuous increase in diabetic complications and an increase in the life expectancy of diabetic patients. Chronic degenerative diseases such as diabetes are increasing whereas the life expectancy of people is being extended due to the change in eating habits resulting from rapid economic development.
In Korea, type 2 diabetes cases account for more than 99% of total diabetes cases, and type 1 diabetes cases account for less than about 1, which are different from those in foreign counties in which type 2 diabetes cases account for about 90% and type 1 diabetes cases account for about 10%. Diabetes is caused by a variety of factors, including heredopathia (family disease history accounts for about 20% of the cases) and circumstance, ages (40-49 years old occupy about 60%), obesity, reduced immunity, drug abuse, and stress. Although the mechanism of onset of diabetes has not been clearly found, it is known that diabetes is caused by multiple genetic factors, except for several types of diabetes (e.g., MODY), and there is a limit to find genes which are consistently involved in diabetes. In other words, the onset of diabetes is associated with various genes, and many new genes involved in the onset of diabetes are currently being found.
Because diabetes is caused by various mechanisms, various methods are used to treat diabetes. In addition, conventional methods for treating diabetes do not exhibit satisfactory effects in many cases, and thus a new method for treating diabetes is required. Studies on diabetes therapeutic agents have been made mainly to develop agents for treating type 2 diabetes accounting for more than 90% of diabetes cases (see Tables 1 and 2).
TABLE 1Status of development of diabetes-associated drugs in KoreaName of Subject ofcompanyDevelopmentPhaseRemarksSamjin Pharm Development ofPreclinicalNew drugCo., Ltd.diabetes therapeuticdevelopmentagent from naturalsubstancesDifferentiation ofInvestigationNew drugembryonic stem cellsdevelopmentinto pancreatic beta-cellsSK Co., Ltd.DiabetesApplicationNew drugdevelopmentYuyu Pharm YYGGInvestigationNew drugCo., Ltd.developmentYuhan Pharm BiochipApplicationImprovement,Co., Ltd.diagnosisChong Kun DangGenetic recombinantPhase IIIImproved Pharmaceutical human insulinnew drugCo., Ltd.Neomary tabletMarketedImproved new drugHanmi Pharm HM80200DevelopmentPharmaceuticalCo. Ltd.ingredientExcerpt:2004 - Pharmaceutical Industry White Paper, Korea Health Industry Development Institute, December 2004
There have been many studies on insulin secretion stimulators (pirogliride, linogliride, 2,4-diamino-5-cyano-dibromopyridine, incretin, repaglinide, nateglinide), insulin action enhancers (troglitazone), insulin resistance improvers, drugs exhibiting insulin-like effects in target tissue (pirogliride, linogliride, dichloroacetate, insulin lispro, insulin aspart), luconeogenesis inhibitors (lipase inhibitors, carnitine transferase inhibitors, beta-oxidation inhibitors), agents delaying carbohydrate absorption (dietary fiber, alpha-glucosidase inhibitors), and amylin analogues (pramlintide).
Some of these substances are currently being marketed, but a significant number of these substances are in experimental stages or toxicity test stages. Particularly, it is expected that fast-acting insulin secretion stimulators and insulin resistance improvers, developed in view of biorhythm, will be one of the effective treatment methods of diabetes and that the development of these drugs will be active in the future.
In addition, studies on the causes of diabetes have been conducted for past ten years under the presumption that insulin resistance results from defects in insulin receptors. Currently, studies are being directed toward insulin signaling systems.
TABLE 2Status of development of new drugs for treating diabetesMechanisms Clinical Phasesof ActionLIIIIIIPLeading companiesα-Glucosidase 31Bayer, Takeda, Chong inhibitorKun DangInsulin agonist13511427Chiron, Eli Lilly, IDEA Zymo-Genetics, Aventis, Novo Nordisk, Akzo Nobel, Biobras, Alkermes, Merk KGaAGlucagon like1414Amylin, Eli Lilly, Novo peptide-1Nordisk, Restoragen, agonistZealandPharmaceuticalsβ3-Adrenoreceptor 121Dainippon, Asahi Kasei,agonistGlaxoSmithKlineDipeptidyl peptide 21Bristol-Myers Squibb, NovatisIV inhibitorPeroxisome 226Novatis, Kyorin, BMS,proliferatorGlaxoSmithKlineactivated receptor α agonistProtein tyrosine17Wyeth, ISIS Pharmaceuticalphosphatase-1B inhibitorLeptin stimulator11Amgen, TularikMelanocortin-4 1Neurocrine BiosciencesagonistAMPK stimulant2211Andrx, Merck KGaA, FlamelTechnologiesPeroxisome 349GlaxoSmithKline, proliferatorSamchundang, BMS,activated receptor Japan Tabacco, Dr Reddy'sγ agonistKyorinExcerpt: Trends in Health Industry & Technology, “Recent Trends in Studies on Diabetes Therapeutic Agents”, 2003
It was reported that, when the activities of PTP-1b (protein tyrosine phosphatase-1b) in the adipocytes of persons with obese type 2 and non-obese type 2 diabetes were examined, the expression levels of the protein were 3 times and 5.5 times, respectively, than that in the normal group, and that the activities of the protein were 71% and 88% of that in the normal group, respectively. Recently, it was reported that PTP-1b knockout mice showed increased sensitivity to insulin and resistance to high-fat diets. In addition, based on a number of studies reported recently, it appears that a substance which inhibits the activity of PTP-1b can increase sensitivity to insulin in target cells to overcome insulin resistance. In the Korea Chemical Bank, high-throughput random screening has been carried out in order to develop PTP-1b inhibitors from tens of thousands of compounds which have not yet been developed into drugs.
Meanwhile, leptin is released from adipocytes into blood, passes through the brain-blood barrier and then acts as a receptor in the central nervous system to suppress food intake, reduce bodyweight and promote energy consumption. Thus, based on the new finding that PTP-1b regulates the activity of leptin itself, it is expected that PTP-1b will exhibit a synergistic effect with a leptin agonist (Koren, S., Best Pract. Res. Clin. Endocrinol. Metab., 21:621, 2007).
Thus, the importance of PTP-1b inhibitors in the development of agents for treating obesity or obese type 2 diabetes is increasing. In recent years, pioneer compounds of PTP-1b inhibitor found by HTS (high-throughput screening) were reported. Until now, studies on PTP-1b and the development of PTP-1b inhibitors have not been clinically successful. However, as shown in Table 3 below, PTP-1b inhibitors are being developed by many research groups and companies.
TABLE 3PTB-1b inhibitors being developedNames ofMedicalDevelopmentMechanismsdrugsCompaniesPhasesOthersProtein tyrosineErtiprotafibWyethPhase IIBenzenepropanoic acidphosphatase(discontinued)1B inhibitorSIS-113718ISISpreclinical2nd-generation antisensePharmaceuticalsPTP-1b inhibitorOS-86839OntogenpreclinicalSelective non-peptideinhibitor of PTP-1bPTP-1b AbbottpreclinicalPhosphastase-1B inhibitorinhibitorPTP-1b ArraypreclinicalPTP-1b inhibitorinhibitorBioPharmaPTP-1b StructuralpreclinicalOrally-active selectiveinhibitorBioinformaticsPTP-1b inhibitorPTP-1b KakenpreclinicalOrally-active PTPase inhibitorinhibitorPharmaceuticalsExcerpt:Pharmaproject, 2002
However, most PTP-1b inhibitors were developed as non-hydrolyzable phosphotyrosine mimetics targeting the active sites of positively charged PTP-1b, and thus have low selectivity and bioavailability (Liu, S. et al., J. Am. Chem. Soc., 130:17075, 2008).
Accordingly, the present inventors have made extensive efforts to develop agents effective for treating obesity and diabetes, and as a result, found that sodium lobarate, which is a salt of lobaric acid separated from an extract of the Antarctic lichen Stereocaulon alpinum, is water-soluble and can be easily applied, and in addition to this sodium lobarate, newly synthesized Lobarin and Lobarstin inhibit PTP-1b more effectively than lobaric acid, and act selectively only on PTP-1b among protein tyrosine phosphatases, and also show anti-diabetic effects when they are administered to disease model animals, thereby completing the present invention.